Development of a method of suppressing immune response is very important for preventing rejection response in organ or cell transplantation, and treating and preventing various autoimmune diseases. Compounds that are conventionally used for suppression of immune response are based on either mechanism of action: (1) attacking a specific immune cell to remove the cell from the immune system, or (2) inhibiting the ability of an immune cell to respond to cytokine, thereby reducing the number of cells involved in immune response. As the number of responding cells reduces, the immune system is disabled to give a normal responding reaction, so that the immune response is suppressed.
To be more specific, the group of compounds based on the first mechanism of action will inhibit nucleotide synthesis in immune cells and stop metabolism and immune activity of the cells. This group includes azathioprine (Non-patent document 1), mizoribine (Non-patent document 2), mycophenolic acid (hereinafter, also abbreviated as “MPA,” Non-patent document 3), brequinar sodium (Non-patent document 4), leflunomide, and methotrexate. However, these compounds face the problem that they are likely to cause toxic side effects.
The group of compounds based on the second mechanism of action includes cyclosporine A (hereinafter also abbreviated as “CsA”), tacrolimus (hereinafter also abbreviated as “FK506”) and rapamycin (Non-patent document 5) and the like. These compounds will inhibit synthesis of cytokine such as IL-2, to thereby disable induction of proliferation and differentiation of effector cells and inhibit immune response. On the other hand, rapamycin blocks a cytokine signal from acting on an immune cell.
In order to mitigate side effects associated with individual immunosuppressive agents, therapies using either CsA or FK506, together with other immunosuppressive agent such as azathioprine or mizoribine or steroids (Non-patent document 6), (Non-patent document 7) or steroids have widely conducted, however, they do not always show sufficient immunosuppressive effect without representing toxic side effects.
As to an amino propanediol derivative having immunosuppressive activity, combinational effect of FTY720 and calcineurin inhibitor is known (Patent document 1). However, it is important to develop new agents for better expression of action or for reduction of side effect.
[Non-patent document 1] Nature, 183: 1682 (1959).
[Non-patent document 2] J. Clin. Invest., 87:940 (1991).
[Non-patent document 3] Pharm. Res., 7: 161 (1990).
[Non-patent document 4] Transplantation, 53: 303 (1992).
[Non-patent document 5] N. Eng. J. Med., 321:1725 (1989); Transplant. Proc., 23: 2977 (1991).
[Non-patent document 6] Transplant. Proc., 17: 1222 (1985).
[Non-patent document 7] Clin. Transplant., 4: 191 (1990).
[Patent document 1] Japanese Patent Laid-Open Publication No. Hei 11-80026